PRSS contributes to cetuximab resistance in colorectal cancer

Tan, Zhaoli; Gao, Lihua; Wang, Yan; Yin, Huihui; Xi, Yongyi; Wu, Xiaojie; Shao, Yong; Qiu, Weiyi; Du, Peng; Shen, Wenlong; Fu, Ling; Jia, Ru; Zhao, Chuanhua; Zhang, Yun; Zhao, Zhihu; Sun, Zhiwei; Chen, Hongxing; Hu, Xianwen; Xu, Jianming; Wang, Youliang

In this study, we showed that PRSS1 expression levels are highly correlated with the sensitivity of colon cancer cells to cetuximab and the response of patients with mCRC to cetuximab therapy. Detailed mechanistic analysis indicated that PRSS can cleave cetuximab and other mAbs, including bevacizumab and trastuzumab, leading to antibody resistance. Cetuximab or bevacizumab combined with serine peptidase inhibitor Kazal type 1 (SPINK1), a PRSS inhibitor, inhibited cell growth more efficiently than cetuximab or bevacizumab alone in xenograft models. We also identified and preliminarily validated the significant association between the serum PRSS1 levels of patients with mCRC and the lack of response to cetuximab therapy. PRSS levels in the serum of 64 healthy individuals and 156 patients with mCRC were analyzed, and poor efficacy of antibody therapy was observed in patients with aberrant PRSS expression. Using systematically characterized clinical data from patients with mCRC, we subdivided the patients into two major subgroups according to the serum PRSS1 level and found significant differences in progressionfree survival (PFS). To validate our findings, we used The Cancer Genome Atlas (TCGA) database to examine whether the clinical outcomes of patients who received antibody monotherapy were associated with PRSS expression. Consistent with the results of our patients treated with cetuximab, we found that patients with low PRSS1 or PRSS3 expression had longer PFS than those with high PRSS1 or PRSS3 expression. Together, our findings indicate that PRSS plays an essential role in the development of cetuximab resistance in patients with mCRC and may be a candidate biomarker of the response to mAbs such as cetuximab, bevacizumab, and trastuzumab. In particular, we also presume that combining a PRSS inhibitor and mAbs may be a viable option for cancer patients with a relatively high PRSS level.